Current Medicinal Chemistry - Volume 15, Issue 11, 2008

Cancer chemoprevention refers to the use of pharmacological agents to inhibit, delay or reverse the multi-step process of carcinogenesis. The last two decades in particular have witnessed explosive growth in this emerging field of cancer chemoprevention. Extensive efforts to evaluate possible application of various chemopreventive agents, in individuals at high risk of neoplastic development have been carried out. Epidemiological studies suggest a protective role of several agents in reducing the risk of cancer. The protective action of all these agents is explained as a combination of various proposed mechanisms involving anti-oxidant, anti-inflammatory, immunomodulatory action, apoptosis induction, molecular association with carcinogen, cell cycle arrest, cell differentiation induction, antimicrobial effect, and anti- angiogenesis etc. Large numbers of candidate substances such as phytochemicals and their synthetic derivatives have been identified by a combination of in vitro and in vivo studies in a wide range of biological assays. However, a comprehensive description of these chemopreventive agents has not been extensively reviewed. In this review we discuss cancer chemopreventive agents in relation to their source, efficacy in cancer chemopreventive action in vivo and epidemiological data. The experimental carcinogenesis studies in different biological models, in addition to the contribution from our laboratory are summarized.

Cytotoxic nucleoside analogues are clinically important anticancer drugs. These agents behave as antimetabolites, compete with physiologic nucleosides, and, consequently, interact with a large number of intracellular targets to induce cytotoxicity. Nucleoside analogues share some general common characteristics, namely in terms of requiring transport by specific membrane transporters and intracellular metabolism. However these compounds differ in regard to the preferential interaction with certain targets which may explain why some compounds are more effective against rapidly proliferating tumours and others on neoplasia with a more protracted evolution. Purine and pyrimidine analogues are widely used not only as antileukaemic agents, but also as cytotoxic agents to treat solid tumours. However, the clinical use of these compounds is limited by important side-effects and primary or acquired drug resistance. Thus, there is an unmet medical need for the development of new antimetabolites and for technologies allowing a more suitable and effective administration of nucleoside analogues for the treatment of cancer patients. Here, we will review literature data concerning the recent development of novel purine nucleoside analogues (clofarabine, nelarabine and forodesine) and pyrimidine nucleoside analogues (troxacitabine, sapacitabine, CP-4055, 3'-C-ethynylcytidine and 5-azapyrimidines) that are in evaluation at the clinical level.

Acquired immunodeficiency syndrome (AIDS) remains, after 25 years of its discovery, as one of the major threats to human life. Reverse Transcriptase is an essential enzyme for virus replication, and therefore constitutes a major target in HIV-1 therapy. Among the different types of drugs targeting RT, the nonnucleoside reverse transcriptase inhibitors (NNRTIs) act by binding in an induced- fit allosteric pocket. In this review, we explore the several NNRTIs' structures and binding interactions, as well as their mechanisms of action. The conformational changes that they cause in RT and their effects on the topology of the active site are discussed. The emergence of mutant, resistant viruses is analysed, focussing on the mutations responsible for the loss of antiviral efficacy of NNRTIs. Explanations for the role of those mutations are presented. Emergent drugs in the pipeline, together with the underlying strategies for drug development, are also analysed.

A number of lectins that bind high-mannose carbohydrates on the surface of the envelopes of virus has been found to have antiviral activity. In particular, some algal lectins such as Cyanovirin-N, Microcystis viridis lectin, Scytovirin, Griffithsin and Oscillatoria agardhii agglutinin, exhibit high anti-HIV activity, and provide an alternative route to prevention of HIV transmission. This review focuses on the structural property, antiviral activity and possible mechanism of these lectins, and future challenges for potential prophylactic or therapeutic applications are also discussed.

Considerable research has been devoted to the role of the adaptive immune system in the pathogenesis of autoimmune inflammatory demyelination (AID). AID is thought to occur spontaneously in patients with multiple sclerosis (MS), a common cause of neurological disability. AID is also observed in the best characterized animal model of MS, experimental autoimmune encephalomyelitis (EAE). The adaptive immune system recognizes and responds to antigens via highly specific T-cell receptors. Myelin-reactive T-cells may initiate pathological immune responses that lead to central nervous system damage in MS and EAE. By contrast, the innate immune system recognizes evolutionarily conserved structures that are common to invading pathogens with high efficiency for rapid recognition and elimination of viruses, bacteria, and fungi. This recognition is mediated by pattern-recognition receptors such as Toll-like receptors (TLRs) expressed on cells of the innate immune system (dendritic cells and CNS-resident cells, such as microglia) that have the potential to activate autoimmune responses by inducing the production of inflammatory cytokines and chemokines. Conversely, the innate immune system can also regulate autoimmune inflammation by inducing the production of immunoregulatory molecules such as type I interferons, which are currently used in the treatment of MS. We review the evidence that TLRs can exacerbate or regulate AID and discuss the therapeutic potential of targeting either process.

Natural toxins are the product of a long-term evolution, and act on essential mechanisms in the most crucial and vital processes of living organisms. They can attack components of the protein synthesis machinery, actin polymerization, signal transduction pathways, intracellular trafficking of vesicles as well as immune and inflammatory responses. For this reason, toxins have increasingly being used as valuable tools for analysis of cellular physiology, and in the recent years, some of them are used medicinally for the treatment of human diseases. This review is devoted to protein toxins of bacterial origin, specifically those toxins that are currently used in therapy or those under study for their potential clinical applications. Bacterial protein toxins are all characterized by a specific mechanism of action that involves the central molecular pathways in the eukaryotic cell. Knowledge of their properties could be used for medical purposes.

The large Ca2+-activated K+ channel (BK channel) reflects per excellence the dilemma of the molecular target driven drug discovery process. Significant experimental evidence suggests that the BK channels play a pivotal and specific role in many pathophysiological conditions supporting the notion that the channel represents an innovative and promising drug target. However, after more than ten years of intense research effort both in academia and industry, scientists have yet to witness the approval of a single BK channel modulator for clinical use. On the contrary, three BK openers that were progressed to clinical development have recently been discontinued (NS8, BMS204352 and TA1702) and, at the present time, only one drug candidate targeting BK channels (andolast) remains in the early phases of clinical development. Since biological studies keep strengthening the concept of BK channels as a potentially attractive target, the design and synthesis of potent and selective BK modulators continue based on novel chemical ideas. A comprehensive overview of BK channel modulators is therefore timely and important to the current medicinal chemist for review, summary, and classification of the multitude of chemical entities claimed to be BK-modulating agents. Such chemical entities are, herein, classified by both origin and chemical structure in 1) Endogenous BK channel modulators and structural analogues 2) Naturally-occurring BK channel inhibitors and blockers 3) Synthetic BK channel inhibitors and blockers 4) Marketed and/or investigational drugs with BK-modulating side properties and structural analogues 5) Naturally-occurring BK channel openers and structural analogues 6) Synthetic BK channel openers. This review is intended to provide readers with current opinion on the BK channel as a drug target, the chemical structures of BK channel modulators, the structural and chemical features involved in the BK channel modulating activity and, where and when possible, with highlights of structure-activity relationships.